Immunomodulation and Vaccine Optimization against Chlamydia

描述（由申请人提供）：沙眼衣原体是一种主要的传染性细菌，在世界范围内引起性传播疾病（STD）。2007年，美国疾病预防和控制中心报告了1,108,374例衣原体感染。妇女的并发症包括盆腔炎、异位妊娠和非自愿输卵管因素不孕。最近的研究发现，通过抗菌药物治疗减少感染会增加人类的再感染率，实际上可能会加剧生殖道内的病理。这些发现强调需要一种有效的预防生殖器衣原体感染的疫苗。衣原体疫苗工作的一个主要挑战是了解控制保护性反应和致病性反应的免疫调节机制。本研究的主要目的是确定IL-10缺陷dc产生的免疫调节分子在促进对生殖器衣原体感染的保护性免疫反应和消除与感染相关的免疫病理中的作用。了解这些分子的作用机制有助于设计针对衣原体的药物和有效疫苗的靶向免疫调节策略。我们将通过两个具体目标来实现这些目标。目的1：确定衣原体脉冲IL-10缺陷dc中α -烯醇化酶和脂肪酸结合蛋白上调在生殖器衣原体感染的保护性免疫应答中的作用。我们的工作假设是，在衣原体脉冲的IL-10缺陷DC中，分子上调在DC快速成熟和Th1细胞激活中起作用。研究建议有；一个)。目的：探讨α -烯醇化酶和脂肪酸结合蛋白在体外成熟标志物DC获取和APC功能增强中的作用。b)。目的：探讨α -烯醇化酶和脂肪酸结合蛋白在体外和体内免疫刺激作用的细胞信号传导机制。目的2：确定衣原体脉冲IL-10KO BMDCs中含有CARD （ASC）下调的凋亡相关斑点样蛋白在体内和体外衣原体感染期间保护病理性免疫反应中的作用。我们的工作假设是，在衣原体脉冲IL-10缺陷dc中下调的分子在病理性免疫反应中发挥作用。研究建议有；一个)。探讨APC在衣原体诱导输卵管病变和不孕中的作用及APC功能增强的作用。b)探讨ASC在dc免疫调节功能中的作用。这些研究的结果将有助于开发针对衣原体的药物和疫苗，这将对控制和预防生殖器衣原体感染和后遗症具有重大意义。

DESCRIPTION (provided by applicant): Chlamydia trachomatis is a major infectious bacterial agent that causes sexually transmitted disease (STD) worldwide. In the United States 1,108,374 Chlamydia infections were reported to the Centers for Disease Prevention and Control in 2007. Complications in women include pelvic inflammatory disease, ectopic pregnancy and involuntary tubal factor infertility. Recent studies have discovered that decreasing the infection through antimicrobial treatment increases the re-infection rate in humans and may actually exacerbate the pathology within the reproductive tract. These findings highlight the need for an effective vaccine against genital Chlamydia infection. A major challenge in Chlamydia vaccine efforts is to understand the immune regulatory mechanisms governing the protective versus the pathogenic responses. The main objective of this proposal is to define the roles of immunomodulatory molecules produced by IL-10 deficient DCs in promoting a protective immune response against genital Chlamydia infection and eliminating the immunopathology associated with the infection. The knowledge of the mechanism of action of such molecules could lead to targeted immunomodulatory strategies in designing drugs and efficacious vaccines against Chlamydia. We will accomplish these objectives using 2 specific aims. Aim 1: To define the role of alpha-enolase and fatty acid-binding protein up-regulated in Chlamydia-pulsed IL-10 deficient DCs in the protective immune response against genital Chlamydia infection. Our working hypothesis is that molecules up-regulated in Chlamydia-pulsed IL-10 deficient DCs play a rule in rapid DC maturation and Th1 cell activation. Study proposal are; a). To investigate the role of alpha- enolase and fatty acid-binding protein in DC acquisition of maturation markers and enhanced APC function in vitro. b). To investigate the cell signaling mechanism of immunestimulatory action of alpha-enolase and fatty acid-binding protein in vitro and in vivo. Aim 2: To define the role of apoptosis-associated speck-like protein containing a CARD (ASC) down regulated in Chlamydia-pulsed IL-10KO BMDCs in protecting against the pathological immune responses during a Chlamydia infection in vivo and in vitro. Our working hypothesis is that molecules down-regulated in Chlamydia-pulsed IL-10 deficient DCs play a rule in pathological immune responses. Study proposal are; a). To investigate of the role of ASC DC acquisition of maturation markers and enhanced APC function and the pathogeneses of Chlamydia induced tube pathology and infertility. b) To investigate the role of ASC in the immunoregulatory function of DCs. Results from these studies will aid in the development of drugs and vaccines against Chlamydia, which will have significant implications for controlling and preventing genital Chlamydia infections and sequelae.